Vol. 29, Issue 9, 1216-1220, September 2001

Metabolism of Vanoxerine, 1-[2-[bis(4-Fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) Piperazine, by Human Cytochrome P450 Enzymes

Svetlana A. Cherstniakova, Daoqin Bi, Daniel R. Fuller, Jurij Z. Mojsiak, Jerry M. Collins, and Louis R. Cantilena

Division of Clinical Pharmacology and Medical Toxicology, Uniformed Services University of the Health Sciences, Bethesda, Maryland (S.A.C., D.B., D.R.F., L.R.C.); National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (J.Z.M.); and Laboratory of Clinical Pharmacology, Center for Drug Evaluation, United States Food and Drug Administration, Rockville, Maryland (J.M.C.)

Vanoxerine (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine; GBR12909) is a promising agent for the treatment of cocaine dependence. Knowledge of the major pathway for GBR12909 metabolism is important for prediction of the likelihood of drug-drug interactions, which may affect the therapeutic clinical outcome, when this agent is used in cocaine-dependent individuals receiving multiple drug therapy. We studied biotransformation of GBR12909 in human liver microsomes (n = 4), human hepatocytes, and microsomes containing cDNA-expressed human P450 isoforms with GBR12909 concentrations within the range of steady-state plasma concentrations detected in healthy volunteers. A high-pressure liquid chromatography assay was used to measure parent GBR12909 and its primary metabolite. GBR12909 was metabolized by human liver microsomes, hepatocytes, and cDNA-expressed human P450s to a single metabolite. Ketoconazole, a selective inhibitor of CYP3A, reduced GBR12909 biotransformation in human liver microsomes and primary hepatocytes by 92 ± 2 and 92.4 ± 0.4%, respectively. Quercetin (an inhibitor of CYP2C8/3A4) was a less effective inhibitor producing 62 ± 22% inhibition in human liver microsomes and 54 ± 35% in hepatocytes. Other P450 selective inhibitors did not decrease GBR12909 biotransformation more than 29% in either human liver microsomes or hepatocytes with the exception of chlorzoxazone (CYP2E1), which inhibited GBR12909 biotransformation by 71.4 ± 18.5% in primary human hepatocytes. Ciprofloxacin (CYP1A2), sulfaphenazole (CYP2C9), quinidine (CYP2D6), chlorzoxazone (CYP2E1), and mephenytoin (CYP2C19) did not demonstrate statistically significant inhibition (p > 0.05) of GBR12909 biotransformation in liver microsomes. cDNA-expressed P450 3A4 metabolized GBR12909 to a greater extent than 2C8 and 2E1. These data suggest the possibility that multiple P450 isoforms may be involved in human GBR12909 metabolism but that CYP3A appears to be the major enzyme responsible for human GBR12909 biotransformation.